DESCRIPTION: (Scanned from the applicant's description) The prevalence of obesity has risen dramatically among all segments of the U.S. population in the last two decades. Recent studies have established a role for melanin-concentrating hormone (MCH) in the control of feeding behavior and body weight. For example, direct central administration of the MCH peptide in rats increases feeding. Also, mice that lack the MCH gene eat significantly less than control mice and have a 25-30 percent reduction in body weight. These observations provide a compelling basis for the development of MCH antagonists as novel drug treatments for obesity and diabetes. In preliminary experiments, we have identified a number of compounds with low micromolar affinity for the MCH receptor, including compounds that have affinities below the micromolar range. In Phase I, we propose a high throughput parallel synthesis approach to generate small molecule libraries in order to develop multiple leads with high affinity. We will also investigate the functional effects of these compounds and determine their specificity for the MCH receptor compared to related receptors. Finally, we will examine selected compounds in a rat MCH-induced feeding model for their ability to block MCH in vivo. The specific aims proposed in Phase I are designed to generate potent small molecule MCH receptor antagonists, together with the data necessary to support the development of these antagonists into valid clinical candidates in Phase II. PROPOSED COMMERCIAL APPLICATION: This research, if successful, will result in small molecule antagonists of the melanin- concentrating hormone receptor that selectively inhibits the feeding response. Orally active forms of a small molecule MCH receptor antagonist would provide a novel therapeutic strategy for indications such as obesity and diabetes.